Familial Mediterranean fever


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Familial Mediterranean fever

  1. 1. Familial Mediterranean Fever By :Rasha Al-Dabbagh Intern doctor at Al-Remal PHCC
  2. 2. # Objectives • Introduction • Background & Pathophysiology • Clinical Manifestations • Complications “Amyloidosis” • Investigations • Differential Diagnosis • Diagnosis • Treatment • Prognosis
  3. 3. # Introduction • FMF is the prototype of a group of inherited “autoinflammatory” diseases – hereditary recurrent fever syndromes- that are characterized by recurrent episodes of fever with serosal, synovial, or cutaneous inflammation and, in some individuals, the eventual development of systemic AA amyloidosis.
  4. 4. # Background & Pathophysiology • : 2:1 • Frequency depends on ethnicity. It affects people originating from around the Mediterranean Sea. • Sephardi Jews (and, to a much lesser extent, Ashkenazi Jews), Cypriots, Turks, Armenians, Italians & Arabs. • Occasional cases are found in absence of known Mediterranean ancestry.
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  6. 6. # • FMF is recessively inherited, but +ve FHx can only be elicited in 50% of cases. • Carrier frequencies reach as high as 1:3 among affected populations, suggesting that not all mutations have equal penetrance. • Most patients have only a single demonstrable MEFV/16p13.3 mutation on DNA sequencing.
  7. 7. # • The FMF gene encodes a 781-amino acid, 95 kDa protein denoted pyrin (or marenostrin) that is expressed in granulocytes, eosinophils, monocytes, dendritic cells, synovial & peritoneal fibroblasts. • Through a number of mechanisms, pyrin regulates caspase-1 [ IL-1 -converting enzyme] & thereby IL-1 secretion. • Ineffective pyrin doesn't inhibit inflammation normally & lead to excessive IL-1 production.
  8. 8. # Clinical Manifestations • Acute attacks: • Age of onset: Febrile episodes may begin in early infancy; 90% of pts have 1st attack by age 20. • Duration: generally 1-4 days. Arthritic attacks tend to last longer. • Frequency: sometimes occur with great regularity, but more often the frequency varies over time, ranging from once every few days to several years. • E&R factors: often unpredictable. Some patients relate them to physical exertion, emotional stress, or menses; pregnancy may be associated with remission.
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  10. 10. # • There are 7 types of attacks. 1. Fever: – Nearly always present. – Severe hyperpyrexia & febrile seizures may be seen in infants. – In 25% it is the only manifestation especially in young children.
  11. 11. # 2. Abdominal attacks: 90% – Acute abdominal pain & signs of peritonitis -resembling appendicitis or choleycystitis. – May lead to unnecessary laparotomy & appendectomy. – Severity is variable. – In many cases, patients develop constipation during attack & diarrhea after attack resolves. – CT scan may show small amount of fluid in abdominal cavity. A sterile, neutrophil-rich peritoneal exudate is present. Adhesions & ascites are rare.
  12. 12. # 3. Chest attacks: – Pleuritis (25-80%), Pericarditis (rare). – Usually manifest as unilateral, sharp, stabbing chest pain that makes it difficult to breathe or lie flat. Friction rub is rare. – Radiographs may show atelectasis or effusion. – Thoracentesis demonstrates a neutrophil-rich exudate. – After repeated attacks, pleural thickening may develop. – Symptomatic pericardial disease is rare. Some patients have small pericardial effusions as an incidental echocardiographic finding.
  13. 13. # 4. Joint attacks: 25-75% – Acute Arthritis: • Usually monoarticular, affecting knee, ankle, or hip. • Large sterile neutrophil-rich effusions are frequent, w/o corresponding erythema or warmth. • Joints are normal b/w attacks, permanent damage is unusual & radiographic changes are rare. – Chronic Arthritis: • Before colchicine prophylaxis, chronic arthritis of knee or hip were seen in 5% in those with arthritis. • 10% develop seronegative spondyloarthropathy “chronic sacroiliitis”.
  14. 14. # 5. Cutaneous manifestation: 50% – The most characteristic is erysipelas- like erythema, a raised erythematous rash most common on dorsum of foot, ankle, or lower leg. – Biopsy demonstrates perivascular infiltrates of granulocytes & monocytes.
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  16. 16. # 6. Myalgia: – Exercise-induced (nonfebrile) myalgia is common. – A small % develop a protracted febrile myalgia lasting several weeks. 7. Scrotal attacks: 5% – Unilateral acute scrotal inflammation (of tunica vaginalis) may occur in prepubertal boys & mimic acute scrotum.
  17. 17. # • Aseptic meningitis has been reported, but causal connection is controversial. • Vasculitis, including HSP, PAN & Behçet disease may be seen at increased frequency in FMF. • Episodes of PID in ♀ patients may occur. • Infertility: 1/3 of ♀ FMF patients are infertile & 20-30% of pregnancies result in fetal loss.
  18. 18. # Complications “Amyloidosis” • Before colchicine prophylaxis, systemic amyloidosis was a common complication. • It is caused by deposition of fragment of serum amyloid A, an acute-phase reactant, in kidneys, adrenals, intestine, spleen, lung & testes. • As a result, proteinuria, followed by nephrotic syndrome, & inevitably, death from renal failure may occur& thus renal function should be monitored.
  19. 19. # • Amyloidosis should be suspected in patients who have proteinuria b/w attacks; renal or rectal biopsy is used to establish diagnosis. • Risk factors for developing amyloidosis include: – M694V homozygous genotype, – +ve family hx (independent of FMF mutational status), – SAA 1 genotype, – ♂ gender, – noncompliance with colchicine therapy, – having grown up in the Middle East.
  20. 20. # Investigations • Lab features during attacks are consistent with acute inflammation & include: – ↑ ESR, – ↑ WBC’s, – ↑ Plt (in children), – ↑ CRP, fibrinogen, haptoglobin & serum immunoglobulins. – Transient albuminuria & hematuria may be seen.
  21. 21. # Differential Diagnosis • If a patient is seen during 1st attack, DDx may be broad, narrowed by specific organ involvement. • After several attacks DDx may include: – Other hereditary recurrent fever syndromes; – Syndrome of periodic fever with aphthous ulcers, pharyngitis, and cervical adenopathy (PFAPA); – Systemic-onset juvenile RA or adult Still's disease; – Porphyria; – Hereditary angioedema; – IBD; – & in women, gynecologic disorders.
  22. 22. # Diagnosis • For typical cases, physicians experienced in FMF can often make diagnosis on clinical grounds alone. • Clinical criteria. • Genetic testing can provide a useful adjunct in ambiguous cases or for physicians not experienced in FMF.
  23. 23. # • Genetic testing may be of prognostic value: – M694V homozygotes have an earlier age of onset and a higher frequency of arthritis, rash & amyloidosis. – E148Q variant is usually associated with milder disease. • In cases where genetic testing is inconclusive, clinical judgment is very important, and sometimes a therapeutic trial of colchicine may help to confirm diagnosis. • Genetic testing of unaffected individuals is usually inadvisable, because of the possibility of nonpenetrance & potential impact of a +ve test on future insurability.
  24. 24. # Treatment • Attacks are self-limiting, require analgesia & NSAIDs (e.g. diclofenac). • The TOC is daily oral colchicine, which ↓ attack frequency & intensity, & prevents amyloidosis in compliant patients. • Colchicine is an alkaloid that may interfere with microtubule formation, thereby affecting mitosis and other microtubule-dependent functions. • Colchicine & metabolites are excreted through urinary & biliary tracts.
  25. 25. # • The adult dose of colchicine is 1.2–1.8 mg/d ( ↑ 0.3 mg/day as needed & tolerated; max. 2.4 mg/day) • It causes substantial reduction in symptoms in 2/3 of patients & some improvement in >90%. • Children may require lower doses, although not proportionately to body weight.
  26. 26. # • Common side effects of colchicine include: bloating, abdominal cramps, muscle pain, lactose intolerance, & diarrhea. • They can be minimized by: starting at a low dose & gradually advancing as tolerated, splitting the dose, use of simethecone for flatulence, & avoidance of dairy products. • If taken by “either” parent at time of conception, colchicine may cause a small increase in the risk of trisomy 21 (Down syndrome).
  27. 27. # • Colchicine toxicity include: bone marrow suppression (3-5 days post exposure), acute renal failure, rhabdomyolysis & neuromyopathy (proximal muscle weakness & elevation of creatine kinase). Severe toxicity results in MOF, convulsions, coma & death. • IV colchicine should not be administered to patients taking oral colchicine, because severe fatal toxicity can occur. • Cyclosporine inhibits hepatic excretion of colchicine, sometimes leading to colchicine toxicity in patients who have undergone renal transplantation for amyloidosis.
  28. 28. # • There are no established alternatives for the 5-10% of patients who do not respond to colchicine or cannot tolerate therapeutic dosages, although interferon-α, IL-1 receptor antagonist & TNF inhibitors are investigational. • Bone marrow transplantation has been suggested for refractory FMF, but the risk-benefit ratio is currently regarded as unacceptable.
  29. 29. # Prognosis • Compliant patients with daily colchicine can expect to have a normal lifespan if colchicine is started before proteinuria develops. • Even with amyloidosis, the use of colchicine, dialysis & renal transplantation should extend a patient's life beyond age 50 years.
  30. 30. Thank You For Listening